The Small Molecule Inhibitor of the Wnt-β-Catenin Pathway, CWP232291, Inhibits Tumor Growth in Preclinical Models of Salivary Gland Adenoid Cystic Carcinoma.

Abstract

Salivary gland adenoid cystic carcinoma (ACC) is a rare and challenging form of head and neck cancer, particularly difficult to treat once it progresses to recurrent or metastatic disease. In this study, we evaluate the cytotoxicity and anti-tumorigenic effects of CWP232291, a first-in-class small molecule inhibitor targeting the Wnt-β-catenin signaling pathway. Tumor microarrays of ACC patients and patient-derived xenografts (PDX) were evaluated by immunohistochemistry, RNA-seq, and qRT-PCR analysis for β-catenin. The effects of CWP232291 were determined by cytotoxic, qRT-PCR, and immunoblotting analysis. In vivo anti-tumorigenic effects of CWP232291 were evaluated using cell line xenograft and PDX models. Immunohistochemistry analysis revealed that high β-catenin expression correlated with reduced overall survival in ACC patients. Expression of genes involved in the Wnt-β-catenin pathway was enriched in PDX samples. In vitro cytotoxicity and biochemical assays using MDA-ACC-01 and UM-HACC-2A cell lines revealed that ACC cells were susceptible to CWP232291. Furthermore, CWP232291 treatment attenuated in vivo tumor growth in both cell line xenograft and PDX models. Abnormal Wnt-β-catenin signaling may play an active role in ACC pathogenesis, and its inhibition by CWP232291 may offer therapeutic potential, representing a promising avenue for further investigation.